BIOCHEMISTRY
CRISPR/Cas9
` BIOCHEMISTRY�LABORA BIOCHEMISTRY�LABORATORY TORY TECHNIQUES
53
SECTION II
A genome editing editing tool derived from bacteria. Consists of a guide RNA (gRNA) , which is complementary to a target DNA sequence, and an endonuclease (Cas9), which makes a singleor doubl double-strand e-strand break at at the target site site . Br Break eak imperfectly repaired by nonhomologous nonhomologous end joining (NHEJ) accidental accidental frameshift mutations mutations (“knock-out (“knock-out”) ”) , or or a donor DNA sequence can be added to fill in the gap using homology-directed homology-directed repair (HDR) (HDR) . Not used clinically. Potential applications include removing virulence factors from pathogens, replacing disease-causing alleles of genes with healthy variants, and specifically targeting tumor cells.
Cas9
gRNA
New image
This illustration was edited in Pass 3 Donor DNA NHEJ
3A
3B
HDR
+
Frameshift/inactivation
Edited sequence
Blotting procedures Southern blot
Northern blot
1. DNA sample is enzymatically cleaved into smaller pieces, which which are separated on a gel by electrophoresis, electrophoresis, and then transferred t ransferred to a filter. 2. Filter is exposed expos ed to radiolabeled DNA probe that recognizes and anneals to its complementary complementary strand. 3. Resulting double-stra double-stranded, nded, labeled labeled piece of DNA is visualized when filter is exposed to film. Similar to Southern blot, except that an RNA sample is electrophoresed. Useful for studying mRNA levels, which are reflective of gene expression.
Western blot
Sample protein is separated via gel electrophoresis and transferred to a membrane. Labeled antibody is used to bind to relevant protein.
Southwestern blot
Identifies DNA-binding proteins (eg, proteins (eg, c-Jun, c-Fos [leucine zipper motif]) using labeled double-stranded double-stranded DNA probes.
I: Parents E E R G I D E P
II: Children
Aa
Aa
T O L B
aa
Aa
AA
Genotype Mutant
N R E H T U O S
Normal
SNo W DR oP: SNo Southern DNA Northern R NA NA W estern estern Protein =
=
=
BIOCHEMISTRY
` BIOCHEMISTRY�GENETICS
SECTION II
59
Modes of inheritance
Autosomal dominant
New images
Autosomal recessive
X-linked recessive carrier
X-linked dominant
Mitochondrial inheritance
Often due to defects in structural genes. Many generations, both males and females are affected. A
a
a
Aa
aa
a
Aa
aa
With 2 carrier (heterozygo (heterozygous us)) parents, parents, on average: average: ¼ of children will be affected (homozygous), ½ of children will be carriers, and ¼ of children will be neither affected nor carriers. A
a
A
AA
Aa
a
Aa
aa
Sons of heterozygous mothers have a 50% chance of being affected. No male-to-male transmission. Skips generations. X
X
X
XX
XX
Y
XY
XY
X
X
X
XX
XX
Y
XY
XY
Transmitted through bot h parents. Mothers transmit to 50% of daughters and sons; fat hers transmit to all daughters but no sons. X
X
X
XX
XX
Y
XY
XY
X
X
X
XX
XX
Y
XY
XY
Transmitted only through the mother. All offspring of af fected females may show signs of disease. Variable Variable expression expression in a population population or even within a family due to heteroplasmy.
Often pleiotropic (multiple apparently unrelated effects) and variably expressive (different between individuals). Family history crucial to diagnosis. With one affected (heterozygous) (heterozygous) parent, on average, ½ of children affected.
Often due to enzyme en zyme deficiencies. Usually Usually seen in only 1 generation. Commonly more severe than dominant disorders; disorders; patients often of ten present in childhood. risk in consanguineous families. Unaffected individual with affected sibling has 2/3 probability probability of being a carrier.
Commonly more severe in males. Females usually must be homozygous to be affected.
—formerly known as Hypophosphatemic rickets—formerly vitamin D–resistant D– resistant rickets. Inherited disorder resulting in phosphate wasting at proximal tubule. Results in rickets-like presentation. Other examples: fragile X syndrome, Alport syndrome.
Mitochondrial myopathies—rare disorders;
often present with w ith myopathy, lactic acidosis, and CNS disease, eg, MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). 2° to failure in oxidative phosphorylation. phosphorylation. Muscle biopsy often shows “ragged red fibers” (due to accumulation of diseased mitochondria in the subsarcolemma of the muscle fiber). Leber hereditary optic neuropathy—cell
death in optic nerve neurons subacute bilateral vision loss in teens/young adults, 90% males. Usually permanent. = unaffected male;
= affected ma le le;
= unaffected female;
= affected female.
204
SECTION II
Hepatitis C therapy
DRUG
MICROBIOLOGY
` MICROBIOLOGY�ANTIMICROBIALS
Chronic HCV infection is treated with different combinations combinations of the following drugs; none is approved as monotherapy. Developed based on understanding of HCV replication cycle. Examples of drugs are provided. ME C HANISM
TOXI CI T Y
Inhibits NS5A, a viral phosphoprotein that plays a key role in RNA replication, unknown exact mechanism.
Headache, diarrhea.
Inhibits NS5B, NS5B, an RNA-dependent R NA-dependent RNA polymerase acting as a chain terminator. Prevents viral RNA R NA replication.
Fatigue, headache.
Inhibits NS3/4A, NS3/4A, a viral protease, preventing viral replication. replication.
Grazoprevir: Photosensitivity reactions, rash. Simeprevir: Headache, fatigue.
Inhibits synthesis of guanine nucleotides nucleotides by competitively competitively inhibiting IMP dehydrogenase. dehydrogenase. Used as adjunct in cases refractory to newer medications
Hemolytic anemia, severe teratogen.
NS5A inhibitors Ledipasvir Ledipasvir Ombitasvir Ombit asvir NS5B inhibitors Sofosbuvir Sofosbuvir Dasabuvir Dasa buvir NS3/4A inhibitors Grazoprevir Grazoprevir Simeprevir Sime previr Alternative drugs Ribavirin
Disinfection and sterilization
Goals include the reduction of pathogenic organism counts to safe levels (disinfection (disinfection)) and the t he inactivation of all microbes including spores (sterilization).
Autoclave
Pressurized steam at > 120°C. Sporicidal. May not reliably inactivate prions.
Alcohols
Denature proteins and disrupt cell membranes. Not sporicidal.
Chlorhexidine
Denatures proteins and disrupts cell membranes. Not sporicidal. sporicidal.
Chlorine
Oxidizes and denatures proteins. Sporicidal. Sporicidal.
Ethylene oxide
Alkylating agent. Sporicidal.
Hydrogen peroxide
Free radical oxidation. Sporicidal.
Iodine and iodophors
Halogenation of DNA, RNA, RNA , and proteins. May be sporicidal.
Quaternary amines
Impair permeability of cell membranes. Not sporicidal.
Antimicrobials to avoid in pregnancy
A NTI MIC ROBIAL
ADV ER SE EFFEC T
Sulfonamides
Kernicterus
A minoglycosides
Ototoxicity
Fluoroquinolones
Cartilage damage
Clarit hromycin
Embryotoxic
Tetracyclines
Discolored teeth, inhibition of bone growth
R ibavirin
Teratogenic
Griseof ulvin
Teratogenic
Chloramphenicol
Gray baby syndrome
eally Good Care. SAFe Children Take R eally
218
SECTION II
Granulomatous inflammation
HISTOLOGY
A
MECHANISM
` PATHOLOGY�INFLAMMATION
PATHOLOGY
A pattern of chronic chronic in�ammation. Can be induced by persistent persistent T-cell T-cell response to certain infections (eg, TB), immune-mediated immune-mediated diseases, and foreign bodies. Granulomas “wall off” off ” a resistant resist ant stimulus without completely completely eradicating or degrading it persistent inflammation fibrosis, organ damage. Focus of epithelioid cells (activated macrophages with abundant pink cytoplasm) surrounded by lymphocytes and multinucleated giant cells (formed by fusion of several activated macrophages). Two types: ty pes: Caseating: associated with central necrosis. Seen with infectious in fectious etiologies (eg, TB, fungal). Noncaseating A : no central necrosis. Seen with autoimmune diseases (eg, sarcoidosis, sarcoidosis, Crohn disease).
APCs A PCs present antigens to to CD4+ Th cells and secrete IL-12 IL -12 CD4+ Th cells differentiate dif ferentiate into Th1 cells Th1 secretes IFN- γ macrophage activation Macrophages cytokine secretion (eg, TNF) formation of epithelioid epithelioid macrophages and giant cells. Anti-TNF therapy can cause sequestering granulomas granulomas to break down disseminated disease. Always test for latent latent TB before before starting anti-TNF therapy. therapy. Associated with hypercalcemia due due to 1α -hydroxylase-mediated vitamin D activation in macrophages. Lymphocyte Fibroblast Epithelioid cell APC
Th1
New image
Giant cell
Macrophage
IL-12
IFN-γ
TNF
Q
R
S
This illustration was edited in Pass 3
Antigen
Granuloma ETIOLOGIES
New images
I N F E C T I O US
Bacterial: Mycobacteria (tuberculosis, Mycobacteria (tuberculosis, leprosy), Bartonella henselae (cat henselae (cat scratch disease; stellate necrotizing granulomas g ranulomas), ), anulomatosis is Listeria monocytogenes (gr monocytogenes (granulomatos infantiseptica), Treponema pallidum (3° syphilis) Fungal: endemic mycoses (eg, histoplasmosis) Parasitic: schistosomiasis
N O N I N F E C T I O US
Immune-mediated: Immune-mediated: sarcoidosis, Crohn disease, 1° biliary cholangitis, subacute (de Quervain/granulomatous) Quervain/granulomatous) thyroiditis Vasculitis: Vasculitis: granulomatosis granulomatosis with polyangiitis (Wegener), eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (Churg-Strauss),, giant g iant cell (temporal) (temporal) arteritis, Takayasu arteritis Foreign Foreign material: berylliosis, talcosis, hypersensitivity pneumonitis Chronic granulomatous disease
PATHOLOGY
Immune evasion in cancer
` PATHOLOGY�NEOPLASIA
SECTION II
223
Immune cells can recognize and attack att ack tumor cells. For For successful tumorigenesis, tumor cells must evade the immune system. Multiple escape mechanisms exist: MHC class I expression by tumor cells cytotoxic T cells are unable to recognize tumor cells. Tumor cells secrete immunosuppressive factors (eg, TGF- β) and recruit regulatory T cells to down-regulate immune response. Tumor cells up-regulate immune checkpoint molecules, which inhibit immune response.
Immune checkpoint interactions
Signals that modulate T cell activation and function immune response against tumor cells. Targeted by several cancer immunotherapies. Examples include: Interaction between PD-1 (on T cells) and PD-L1/2 (on tumor cells or immune cells in tumor microenvironment) T cell dysfunction (exhaustion). Inhibited by antibodies against PD-1 (eg, pembrolizumab, nivolumab) or PD-L1 (eg, atezolizumab, durvalumab, avelumab). CTLA-4 CTLA -4 on T cells outcompetes CD28 CD28 for B7 on APCs loss of T cell costimulatory signal. Inhibited Inhibited by ipilimumab ipilimumab (anti-CTLA-4 (anti-CTL A-4 antibody). antibody).
This fact was migrated from Hem/ Onc.
T cell
APC
Ipilimumab
New Fact for 2019
Atezolizumab Durvalumab Avelumab
This illustration was edited in Pass 3
CD28 B7 CTLA-4
Nivolumab Pembrolizumab Antigen
MHC I
TCR
This illustration was edited in Pass 4
Tumor cell
T cell activation PD-1
Cancer epidemiology
PD-L1/2
Skin cancer (basal > squamous >> melanoma) is the most common cancer (not included below). M EN
WO M E N
C H IL D R E N � AG E 0�14�
N OT E S
Cancer incidence
1. Prostate 2. Lung 3. Colon/rectum
1. Breast 2. Lung 3. Colon/rectum
1. Leukemia 2. CNS 3. Neuroblastoma
Lung cancer incidence has in men, but has not changed significantly in women.
Cancer mortality
1. Lung 2. Prostate 3. Colon/rectum
1. Lung 2. Breast 3. Colon/rectum
1. Leukemia 2. CNS 3. Neuroblastoma
Cancer is the 2nd leading cause of death in the United States (heart disease is 1st). 1st).
` CARDIOVASCULAR�ANATOMY
CARDIOVASCULAR
SECTION III
281
` CARDIOVASCU LAR�ANATOMY
Anatomy of the heart A RV LV
RA
pv
LA is the most posterior part of the heart A ; enlargement can cause dysphagia (due to compression of the esophagus) esophagu s) or hoarseness (due (due to compression of the left recurrent lary ngeal nerve, a branch of the vagus nerve). nerve). RV is the most anterior part of the heart and most commonly injured injured in trauma
LA Ao
Pericardium
Consists of 3 layers (from outer to inner): Fibrous pericardium Parietal layer of serous pericardium Visceral layer of serous pericardium pericardium Pericardial Pericardial cavity lies between parietal and visceral layers. Pericardium Pericardium innervated by phrenic nerve.
Pericarditis Pericarditis can cause referred pain to the neck, arms, or one or both shoulders (often left).
LAD LA D and its branches supply anterior 2/3 of interventricular septum, anterolateral anterolateral papillary muscle. LAD LA D supplies anterior of interventricular septum, anterolateral papillary muscle, and anterior surface of LV. Most commonly occluded. PDA supplies AV node (dependent on dominance), posterior 1/3 of interventricular septum, posterior 2/3 walls of ventricles, and posteromedial papillary muscle. Right (acute) marginal artery supplies RV. RCA supplies SA node (blood supply independent of dominance). Infarct may cause nodal dysfunction (bradycardia or heart block).
Dominance: Right-dominant circulation (85%) = PDA arises from RCA. Left-dominant Left- dominant circulation (8%) (8%) = PDA arises from LCX. Codominant circulation (7%) = PDA arises from both LCX and RCA. Coronary blood flow peaks in early diastole.
Coronary blood supply
PV
PV LCA
LA Aorta
New image
LA
LCX OMA
SVC RCA
RA
LAD
IVC
PT Key: AMA = Acute marginal marginal artery LAD = Left anterior descending artery LCA = Left coronary artery LCX = Left circumflex artery OMA = Obtuse marginal artery PDA = Posterior descending descending artery PT = Pulmonary trunk PV = Pulmonary vein RCA = Right coronary artery
SVC
RA
LV RV
IVC AMA
LV RV PDA
Anterior view
Posterior view
CARDIOVASCULAR
` CARDIOVASCULAR�PHYSIOLOGY
SECTION III
283
Cardiac output equations E QUAT IO NS
Stroke volume Ejection fraction Cardiac output
N OT E S
SV = EDV − ESV EF =
SV EDV − ESV = EDV EDV
EF is an index of ventricular contractility ( in systolic HF; usually normal in diastolic HF).
CO = SV × HR Fick principle: rate of O2 consumption CO = (arterial O2 content – venous O2 content)
In early stages of exercise, CO maintained by HR and SV. In later stages, CO maintained by HR only (SV plateaus). Diastole is shortened with HR (eg, ventricular tachycardia) diastolic filling time SV CO.
Pulse pressure
PP = SB SBP – DBP
PP directly proportional to SV and inversely proportional to arterial compliance. compliance. PP in hyperthyroidism, aortic regurgitation, aortic stiffening stif fening (isolated (isolated systolic hypertension in elderly), obstructive sleep apnea ( sympathetic tone), anemia, exercise (transient). PP in aortic aort ic stenosis, cardiogenic shock, cardiac tamponade, advanced HF.
Mean arterial pressure
MAP = CO × TP TPR
MA P (at resting HR) = 2 ⁄ 3 DBP + 1 ⁄ 3 SBP = DBP + 1 ⁄ 3 PP
Starling curve
Exercise Normal ) O C r o ( e m u l o v e k o r t S
Contractility HF + digoxin
HF
Ventricular EDV (preload)
Force Force of contraction is proportional to enddiastolic length of c ardiac muscle fiber (preload). catecholamines, positive contractility with catecholamines, inotropes (eg, digoxin). contractility with loss of myocardium (eg, MI), MI), β -blockers (acutely), non-dihydropyridine Ca 2+ channel blockers, dilated cardiomyopathy.
CARDIOVASCULAR
` CARDIOVASCULAR�PATHOLOGY
311
SECTION III
Vasculitides (continued) EPI D E MI OL OG Y/PR E S EN TAT ION
PATH OLO GY/L ABS
Small-vessel vasculitis (continued)
Eosinophilic granulomatosis with polyangiitis (ChurgStrauss)
Asthma, sinusitis, skin nodules or purpura, peripheral neuropathy (eg, wrist/foot drop). Can also involve heart, GI, kidneys (pauciimmune glomerulonephritis).
Granulomatous, Granulomatous, necrotizing vasculitis va sculitis with eosinophilia G . MPO-ANCA/p-ANCA, IgE level.
Granulomatosis with polyangiitis (Wegener)
Upper respiratory respiratory tract: t ract: perforation of nasal septum, chronic sinusitis, otitis media, mastoiditis. Lower respiratory tract: hemoptysis, cough, dyspnea. Renal: hematuria, red cell casts.
Triad: Focal necrotizing vasculitis Necrotizing granulomas in lung and upper airway Necrotizing glomerulonephritis glomerulonephritis PR3-ANCA/c-ANCA H (anti-proteinase 3). CXR: large nodular densities. Treat with cyclophosphamide, corticosteroids.
Also known as Henoch-Schönlein purpura. purpura. Most common childhood systemic vasculitis. Often follows URI. Classic triad: Skin: palpable palpable purpura on buttocks/ legs I Arthralgias Arthr algias GI: abdominal pain (associated with intussusception)
Vasculitis Vasculitis 2° to IgA immune complex complex deposition. Associated with IgA nephropathy (Buerger (Buerger disease).
Microscopic polyangiitis
Necrotizing vasculitis commonly involving lung, kidneys, and skin with pauci-immune glomerulonephritis glomerulonephritis and palpable palpable purpura. Presentation similar to granulomatosis with polyangiitis but without nasopharyngeal involvement.
No granulomas. MPO-ANCA/p-ANCA J (antimyeloperoxidase). Treat with cyclophosphamide, corticosteroids.
Mixed cryoglobulinemia
Often due to viral infections, especially HCV. Cryoglobulins are immunoglobulins that Triad of palpable purpura, weakness, arthralgias. precipitate in the cold. May also have peripheral peripheral neuropathy and renal Vasculitis Vasculitis due to mixed IgG and IgA immune disease (eg, glomerulonephritis). complex deposition.
Immunoglobulin A vasculitis
A
B
LCC
C
D
E LM
RSC
LCX
LAD AAo
F
G
H
I
J
GASTROINTESTINAL
` GASTROINTESTINAL�PATHOLOGY
SECTION III
371
Esophageal pathologies
Diffuse esophageal spasm
Spontaneous, nonperistaltic (uncoordinated (uncoordinated)) contractions of the esophagus with normal LES pressure. Presents with dysphagia and angina-like an gina-like chest pain. Barium swallow reveals “corkscrew” esophagus. Manometry is diagnostic. Treatment includes includes nitrates and CCBs.
Eosinophilic esophagitis
Infiltration of eosinophils in the esophagus often in atopic patients. Food allergens allergens dysphagia, food impaction. Esophageal rings and linear furrows fur rows often seen on endoscopy. endoscopy. Typically Typically unresponsive to GERD therapy.
Esophageal perforation
Most commonly iatrogenic following esophageal instrumentation. Noniatrogenic causes include spontaneous rupture, foreign body ingestion, t rauma, malignancy. May present with pneumomediastinum pneumomediastinum (arrows in A ). Subcutaneous emphysema may be due to dissecting air (signs include crepitus in the neck reg ion or chest wall). Boerhaave syndrome—transmural, usually distal esophageal rupture due to violent retching. retching.
Esophageal strictures
Associated with caustic ingestion, acid acid reflux, and esophagitis.
Esophageal varices
Dilated submucosal veins (red (red arrows in B C ) in lower 1 ⁄ 3 of esophagus 2° to portal hypertension. Common in cirrhotics, may be source of life- threatening hematemesis.
Esophagitis
Associated with reflux, infection in immunocompromised immunocompromised (Candida: white pseudomembrane D ; HSV-1: punched-out ulcers; CMV: linear ulcers), caustic ingestion, or pill-induced esophagitis (eg, bisphosphonates, tetracycline, NSAIDs, iron, and potassium chloride).
Gastroesophageal reflux disease
Commonly presents as heartburn, regurgitation, regurg itation, dysphagia. May also present as chronic cough, hoarseness (laryngopharyngeal (laryngophar yngeal reflux). Associated with asthma. Transient decreases in LES tone.
Mallory-Weiss Mall ory-Weiss syndrome
Partial thickness, longitudinal lacerations of gastroesophageal junction, confined to mucosa/ submucosa, submucosa, due to severe vomiting. Often presents with hematemesis. Usually found in a lcoholics lcoholics and bulimics.
Plummer-Vinson Plummer-Vinson syndrome
Triad of Dysphagia, Iron deficiency anemia, and Esophageal webs. May be associated with glossitis. Increased risk of esophageal squamous cell carcinoma (“ Plumbers DIE”).
Schatzki rings
Rings formed at gastroesophageal junction, typically due to chronic acid reflux. Can present with dysphagia.
Sclerodermal esophageal dysmotility
Esophageal smooth muscle atrophy LES pressure and dysmotility acid reflux and dysphagia stricture, Barrett esophagus, and aspiration. Part of CREST syndrome. A
B
Aortic T arch E
C
D
New image
esophagus Ao
446
SECTION III
MUSCULOSKELETAL, MUSCULOSKELET AL, SKIN, AND CONNECTIVE TISSUE
A nterior nterior TaloF aloFibular ligament—most common ankle sprain overall, classified as a low ankle sprain. Due to overinversion/supinatio overinversion/supination n of foot. Anterior inferior inferior tibiofibular tibiofibular ligament—most ligament—most common high ankle sprain. A lways lways Tears First.
Ankle sprains
` ANATOMY AND PHYSIOLOGY
Anterior inferior tibiofibular ligament
Fibula
Posterior inferior tibiofibular ligament
Tibia
Posterior talofibular ligament Calcaneus
Anterior talofibular ligament Navicular Cuneiform bones
Talus
Cuboid
Calcaneofibular ligament Tarsals Metatarsals
Signs of lumbosacral radiculopathy
Disc level herniation Nerve root
Phalanges
Paresthesia and weakness related to specific lumbosacral spinal nerves. Intervertebral disc (nucleus (nucleus pulposus) pulposus) herniates posterolaterally through annulus fibrosus (outer (outer ring) into central canal due to thin posterior longitudinal ligament and thicker anterior longitudinal ligament along midline of vertebral bodies. Nerve affected is usually below the level of herniation. L3-L4
L4-L5
L5-S1
L4
L5
S1
This fact was migrated.
This illustration was edited in Pass 2
This illustration was edited in Pass 3
Lumbar pedicle (cut) L4 L4 root L4-L5 disc protrusion L5
Dermatome
L5 root L5-S1 disc protrusion
S1 root
Clinical findings
Weakness of knee extension ↓ patellar reflex
Weakness of dorsiflexion Difficulty in heel walking
Weakness of plantar flexion Difficulty in toe walking ↓ Achilles reflex
This illustration was edited in Pass 3
S2 root
New image
MUSCULOSKELETAL, MUSCULOSKELET AL, SKIN, AND CONNECTIVE TISSUE
` DERMATOLOGY
SECTION III
471
Autoimmune blistering skin disorders
Pemphigus vulgaris This is a new fact.
Bullous pemphigoid Bullous
PATHOPHYSIOLOGY
Potentially Potentially fatal. Most commonly seen in older adults. Type Type II hypersensitivity reaction. IgG antibodies against agains t desmoglein-1 and/or and/or desmoglein-3 (component of desmosomes, which connect keratinocytes in the stratum spinosum).
Less severe than pemphigus vulgaris. Most commonly seen in older adults. Type II hypersensitivity reaction. IgG antibodies against hemidesmosomes hemidesmosomes (epidermal basement membrane; antibodies are “bull “ bullow” the epidermis).
GROSS MORPHOLOGY
Flaccid intraepidermal bullae A caused by acantholysis (separation (separation of keratinocytes, “row of tombstones” on H&E stain); oral mucosa is involved. Nikolsky sign ⊕.
Tense blisters C containing eosinophils; oral mucosa spared. Nikolsky sign ⊝.
IMMUNOFLUORESCENCE
Reticular pattern around epidermal cells B .
Lin Linear ear pa patte ttern at ep epidermal rmal-d -deermal rmal junct unctiion D .
A
B
C
D
Other blistering skin disorders This is a new table.
Dermatitis herpetiformis
Pruritic papules, vesicles, and bullae (often found on elbows, knees, buttocks) A . Deposits of IgA at tips of dermal papillae. papillae. Associated A ssociated with celiac disease. Treatment: dapsone, gluten-free diet.
Erythema multiforme
Associated with infections (eg, (eg, Mycoplasma pneumoniae, pneumoniae, HSV), drugs (eg, sulfa drugs, β -lactams, phenytoin). Presents with multiple types of lesions—macules, papules, vesicles, target lesions (look like targets with multiple rings and dusky center showing epithelial disruption) disruption) B .
Stevens-Johnson syndrome
Characterized by fever, bullae bullae formation and necrosis, sloughing of skin at dermal-epidermal junction (⊕ Nikolsky), high mortality rate. Typically mucous membranes are involved C D . Targetoid skin lesions may appear, as seen in er ythema multiforme. Usually associated with Toxic xic epidermal necrolysis (TEN) E F is more severe form of SJS involving adverse drug reaction. To > 30% body surface area. 10–30% involvement denotes SJS-TEN. A
B
C
D
E
F
490
SECTION III
` NEUROLOGY�ANATOMY AND PHYSIOLOGY
NEUROLOGY AND SPECIAL SENSES
Topographic representation of motor (shown) (shown) and sensory sensor y areas in the cerebral cortex. Distorted appearance is due to certain body regions being more richly innervated and thus having cortical representation.
Homunculus
Motor homunculus Anterior cerebral artery
This illustration was edited in Pass 2
S
E h l o
W b o u w l r d i H e t a n s r L i d t t
Middle cerebral artery
e R i n l
g M i d I n d e d l e x T x
Posterior cerebral artery
h u um b m
F i n g e e r r s s
N e e c ck k Br ow
T r u n k
H i p
Sensory homunculus
e e K n
Ankle Toes
p k i n H u r T
Leg
Foot Toes Genitals
k c d r a e e e d m N H l r w u A o r o m b a h l t S E i s e r
s r s n g e i n F i
g R i n d l e e d i M nd d e x I m b T h u E y e
E y ye lid & ey eball
Nose
Face
Lip Lips
Ja w To Tongue wingg wallo win S wa
New image
r e o W t l e F L i t
lip Upper lip Lower lip T eeth, gu gums Intra-a ra-ab bdominal Ton Tongue Phary arynx
Cerebral arteries—cortical distribution Anterior cerebral artery (supplies anteromedial surface) Middle cerebral artery (supplies lateral surface)
Anterior
Posterior cerebral artery (supplies posterior and inferior surfaces)
Anterior
Posterior Posterior
Watershed zones A
Between anterior and middle cerebral arteries Infarct due to severe hypotension proximal and posterior and middle cerebral arteries upper and lower extremity weakness (“man(cortical border zones) (blue areas in A ); or may in-the-barrel syndrome”) s yndrome”),, higher order visual also occur between the superficial and deep dysfunction (if posterior cerebral/middle cerebral/middle vascular territories of the middle cerebral artery cerebral cortical border zone stroke). (internal border zones) (red areas in A ).
This illustration was edited in Pass 3
NEUROLOGY AND SPECIAL SENSES
` NEUROLOGY�ANATOMY AND PHYSIOLOGY
495
SECTION III
Cranial nerve reflexes R E FL E X
New image
Had to reduce in page to fit column. Labels too small.
AFFEREN T
E F FE R E N T
Corneal
V 1 op ophthal thalm mic (nas nasoci ociliary branch)
Bilateral VII VII (temporal branch—orbicula ularis oculi)
Lacrimation
V 1 (loss of reflex does not preclude emotional emotional tears)
VII
Jaw jerk
V 3 (s (senso ensory ry— —musc uscle spi spindl ndle from from mass masset eter er))
V 3 (motor—masseter)
Pupillary
II
III
Gag
IX
X
Mastication muscles
3 muscles close jaw: Masseter, teM teMporalis, Medial pterygoid. 1 opens: Lateral pterygoid. All are innervated by trigeminal nerve nerve (V 3).
M’s Munch. Lateral Lowers (when (when speaking speakin g of pterygoids with respect to jaw motion). “It takes more muscle to keep your mouth shut.”
Spinal nerves
There are 31 pairs of spinal nerves: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, 1 coccygeal. Nerves C1–C7 exit above the corresponding vertebrae. C8 spinal nerve e xits below C7 and above T1. T1. All other nerves exit below (eg, C3 exits above the 3rd cervical vertebra; L2 exits below the 2nd lumbar vertebra).
Spinal cord—lower extent
In adults, spinal cord ends at lower border of L1–L2 vertebrae. Subarachnoid Space (which contains the CSF) extends ex tends to lower border of S2 S2 vertebra. vertebra. Lumbar puncture is usually performed between L3–L4 or L4 –L5 (level of cauda equina). Goal of lumbar puncture is to obtain sample of CSF without damaging spinal cord. To keep the cord alive alive,, keep the spinal needle between L3 and L3 and L5 L5.. Needle passes through: skin fascia and and fat fat supraspinous supraspinous ligament ligament interspinous interspinous ligament ligament ligamentum flavum epidural space (epidural anesthesia needle stops here) dura mater arachnoid mater subarachnoid space (CSF collection occurs here)
Anterior longitudinal ligament L1
Q R
Posterior longitudinal ligament Conus medullaris
S T U
Cauda equina
V W X Y
S1
Filum terminale
This illustration was edited in Pass 2
504
SECTION III
Aphasia
NEUROLOGY AND SPECIAL SENSES
` NEUROLOGY�PATHOLOGY
Aphasia—higher-order Aphasia—higher-order language deficit deficit (inability (inability to understand/produce/use understand/produce/use language lang uage appropriately); caused by pathology in dominant cerebral hemisphere (usually left). Dysarthria— Dysarthr ia—motor motor inability to produce speech (movement deficit).
Good comprehension Poor comprehension comprehension
Fluent speech
Conduction aphasia
Wernicke aphasia Transcortical sensory aphasia
Nonfluent speech
Broca aphasia
Transcortical mixed aphasia
Transcortical motor aphasia
New image. Reduced to hold page.
This illustration was edited in Pass 2
n i o n i t e t i t i o p r e p e t r o r e P o o d G o T YPE
COMME NT S
Broca (expressive)
Broca area in inferior frontal gyrus gyr us of frontal lobe. Patient appears appears frust rated, insight intact. Broca = Broken Boca (boca = mouth in Spanish).
Wernicke (receptive)
Wernicke Wernicke area in superior superior temporal temporal gyrus of temporal lobe. lobe. Patients Patients do not have insight. insight. W ernicke ernicke is a W a W ord ord salad and makes no sense.
Conduction
Can be caused by damage to ar Cuate fasciculus fa sciculus..
Global
Arcuate fasciculus; fasciculus; Broca and Wernicke Wernicke areas affected.
Transcortical motor
Affects Affect s frontal lobe around around Broca area, but Broca Broca area is spared.
Transcortical sensory
Affects Affect s temporal lobe around Wernicke Wernicke area, but but Wernicke Wernicke area is spared. spared.
Transcortical mixed
Broca and Wernicke areas and arcuate fasciculus remain intact; surrounding watershed areas affected.
Aneurysms Saccular aneurysm A
New image
This table was edited in Pass 2
Abnormal dilation of an artery due to weakening weakening of vessel wall. Also known as berry aneurysm A . Occurs at bifurcations in the circle of Willis. Most common site is junction of ACom and ACA. A ssociated with ADPKD, Ehlers-Danlos syndrome. Other risk factors: advanced age, hypertension, smoking, race ( risk in African-Americans). Usually clinically silent until rupture (most common complication) subarachnoid hemorrhage (“worst headache of my life” or “thunderclap headache”) focal neurologic deficits. Can also cause symptoms via direct compression compression of surrounding structures by growing aneurysm. ACom—comp ACom—compression ression bitemporal hemianopia (compression of optic chiasm); visual acuity deficits; rupture ischemia in ACA distributio distr ibution n contralateral lower extremity ext remity hemiparesis, sensory deficits. MCA—rupture ischemia in MCA distribution dist ribution contralateral upper extremity and lower facial hemiparesis, sensory deficits. PCom—compression ipsilateral CN III palsy mydriasis (“blown pupil”); may also see ptosis, “down and out” eye.
Charcot-Bouchard microaneurysm
Common, associated with chronic hypertension; affects small vessels (eg, lenticulostriate arteries in basal ganglia, gan glia, thalamus) and can cause hemorrhagic intraparenchymal strokes. Not visible on angiography.
Page runs 3 lines long.
` NEUROLOGY�PATHOLOGY
NEUROLOGY AND SPECIAL SENSES
Seizures
Partial (focal) seizures
505
Characterized by synchronized, high-frequency neuronal firing. Variety of forms. Affect Af fect single area of of the brain. Most Most commonly originate in medial temporal lobe. Types: Simple partial (consciousness intact)— motor, sensory, autonomic, psychic Complex partial (impaired consciousness, automatisms)
Generalized seizures
SECTION III
Diffuse. Types: Absence (petit mal)—3 mal)—3 Hz spike-and-wave discharges, no postictal confusion, blank stare —quick, repetitive jerks Myoclonic—quick, m al)—alternating alternating Tonic-clonic (grand mal)— stiffening and movement, postictal confusion, urinary incontinence, tongue biting Tonic—stiffening Atonic—“drop” seizures (falls to floor); commonly mistaken for fainting
Epilepsy—a disorder of recurrent, unprovoked
seizures (febrile seizures are not epilepsy). Status epilepticus—continuous (≥ 5 min) or recurring seizures that may result in brain injury. Causes of seizures by age: Children—genetic, infection (febrile), trauma, congenital, metabolic Adults—tumor, Adults—tumor, trauma, stroke, stroke, infection Elderly—stroke, tumor, trauma, metabolic, infection
Seizure
Partial (focal) seizures
Generalized seizures
2° generalized
Impaired consciousness? consciousness?
New image. Reduced slightly to fit new fact on page.
Simple partial
Complex partial
Tonic-clonic (grand mal)
Tonic
Myoclonic
Atonic
Absence (petit mal)
Altenating stiffening and movement
Stiffening
Quick and repetitive jerks
Drop seizure (falls to floor)
Blank stare no postictal confusion
Tonic phase
Drop Clonic phase
Fever vs heat stroke
Fever
Heat stroke
PATHOPHYSIOLOGY
Cytokine activation during inflammation (eg, infection)
Inability of body to dissipate heat (eg, exertion)
TEMPERATURE
Usually < 40 °C
Usually > 40 °C
COMPLICATIONS
Febril ebrilee seizur seizuree (benign (benign,, usuall usuallyy self-l self-limi imiting ting))
CNS CNS dysfunc dysfunctio tion n (eg, (eg, confusi confusion on), ), end-o end-orga rgan n damage, acute respiratory distress syndrome, rhabdomyolysis
Acetaminophen or ibuprof ibuprofen en for comfort (does (does not prevent future febrile seizures), antibiotic therapy if indicated
Rapid external cooling, rehydration and electrolyte correction
New fact
MANAGEMENT
Crowdproofer feedback. This fact seems out of place here.
NEUROLOGY AND SPECIAL SENSES
` NEUROLOGY�PATHOLOGY
SECTION III
513
Neurocutaneous Neurocutan eous disorders DISO RD ER
G ENE T IC S
Sturge-Weber syndrome
Congenital Affects capill capillary-sized ary-sized blood blood vessels vessels nonhereditary port-wine stain A (nevus flammeus anomaly of neural or non-neoplastic birthmark) in crest derivatives. CN V 1/V 2 distribution; distribution; ipsilateral ipsilateral Somatic mosaicism of leptomeningeal leptomeningeal angioma B seizures/ an activating mutation epilepsy; intellectual disability; episcleral episcleral in one copy of the hemangioma IOP early-onset GNAQ gene. glaucoma.
Tuberous sclerosis
AD, variabl variablee expre expressi ssion. on. TSC1 mutation on chromosome 9 or TSC2 mutation on chromosome 16. Tumor suppressor genes.
Neurofibromatosis AD, 100% penetrance. Mutation in NF1 type I
tumor suppressor gene on chromosome 17 (encodes neurofibromin, a negative RAS regulator) regulator) Mutation in NF2 Neurofibromatosis AD. Mutation tumor suppressor gene type II
PRE SENTATI ON
NOTE S
Hamartomas in CNS and skin, A ngiofibromas ngiofibromas C , Mitral regurgitation, A sh-leaf sh-leaf spots D , cardiac R habdomyoma, habdomyoma,
(Tuberous sclerosis), autosomal dOminant; Mental retardation (intellectual disability), renal A ngiomyolipoma ngiomyolipoma E , Seizures, Shagreen patches. Café-au-lait
spots F , Intellectual disability dis ability,, Cutaneous neurofibromas G , Lisch nodules (pigmented iris hamartomas H ), Optic gliomas, Pheochromocytomas, Seizures/focal neurologic Signs (often from meningioma), bone lesions (eg, sphenoid dysplasia).
Bilateral vestibular schwannomas, juvenile cataracts, meningiomas, ependymomas.
Also known as encephalotrigeminal angiomatosis. SSTURGGE -Weber: Sporadic, port-wine Stain, Tram track calcifications (opposing gyri), Unilateral, intellectual disability (R etardation), etardation), Glaucoma, NAQ Q gene, Epilepsy. GNA HAMARTOMASS. incidence
of subependymal giant cell astrocytomas and ungual fibromas.
Also known as von Recklinghausen disease. 17 letters in “von Recklinghausen.” CICLOPSS.
NF2 affects 2 ears, 2 eyes, and 2 parts of the brain.
on chromosome 22. Deletion on of VHL von Hippel-Lindau AD. Deleti gene on chromosome disease 3p. pVHL
ubiquitinates ubiquitinates hypoxiahypoxia inducible factor 1a.
Hemangioblastomas
(high vascularity with Numerous Numerous tumors, benign and hyperchromatic nuclei I ) in retina, brain malignant. stem, cerebellum, spine J ; A ngiomatosis; ngiomatosis; VHL = 3 letters. HARP. bilateral R enal enal cell carcinomas; Pheochromocytomas.
A
B
C
D
E
F
G
H
I
J
592
SECTION III
Renovascular disease
RENAL
` RENAL�PATHOLOGY
Renal impairment due to ischemia from renal artery stenosis or microvascular disease. renal perf usion (one (one or both kidneys k idneys)) renin angiotensin HTN. Main causes of renal artery stenosis: Atherosclerotic plaques plaques—pr —proximal oximal 1/3rd 1/3rd of renal artery, usually in older males, smokers. Fibromuscular dysplasia—distal 2/3rd of renal artery or segmental seg mental branches, usually young or middle-aged females. Clinically, Clinically, patients can have refractory HTN with negative family history of HTN, H TN, asymmetric renal size, epigastric/flank bruits.
Most common cause of 2° HTN in adults. Other large vessels are a re often involved.
Renal cyst disorders Autosomal dominant polycystic kidney disease
Numerous Numerous cysts in cortex and medulla A causing bilateral enlarged kidneys ultimately u ltimately destroy kidney parenchyma. Presents Presents with flank pain, hematuria, hypertension, urinary infection, progressive renal failure in ~ 50% of individuals. Mutation in PKD1 (85% of cases, chromosome 16) or PKD2 (15% of cases, chromosome 4) . Complications Complications include chronic kidney disease and hypertension (caused by renin production). Associated with berry aneurysms, mitral valve prolapse, prolapse, benign benign hepatic cysts, diverticulosis. Treatment: If hypertension or proteinuria proteinuria develops, treat with ACE inhibitors inhibitors or ARBs. A RBs.
Autosomal recessive polycystic kidney disease
Cystic dilation of collecting ducts B . Often presents in infancy. Associated with congenital hepatic fibrosis. Significant oliguric renal failure in utero can lead to Potter sequence. sequence. Concerns beyond neonatal period include systemic hypertension, progressive renal insufficiency, insufficiency, and portal por tal hypertension from congenital hepatic fibrosis.
Autosomal dominant tubulointerstitial kidney disease
Also known as medullary cystic kidney disease. Causes Causes tubulointerstitial tubulointerstitial fibrosis and progressive renal insufficiency with inability to concentrate urine. Medullary Medullary cysts usually not visualized; smaller kidneys on ultrasound. Poor prognosis.
Simple vs complex renal cysts
Simple Simple cysts cyst s are filled with ultrafiltrate (anechoic (anechoic on ultrasound C ). Very common and account for majority of all renal masses. Found incidentally incidentally and typically ty pically asymptomatic. Complex Complex cysts, including including those that are septated, enhanced, or have solid components components on imaging ima ging require follow-up follow-up or removal due to risk of renal cell carcinoma. A
B
C
652
SECTION III
Cyanide vs carbon monoxide poisoning
RESPIRATORY
` RESPIRATORY�PHYSIOLOGY
Both inhibit aerobic metabolism via inhibition of complex IV (cytochrome c oxidase) hypoxia unresponsive to supplemental O2 and anaerobic metabolism. Both can lead to pink or cherry red skin (usually postmortem finding), seizures, and coma. Cyanide
Carbon monoxide
SOURCE
Byproduct of synthetic product combustion, ingestion of amygdalin (cyanogenic glucoside glucoside found in apricot seeds) or cyanide.
Odorless gas from fires, car exhaust, or gas g as heaters.
TREATMENT
Hydroxocobalamin Hydroxocobalamin (forms cyanocobalamin) cyanocobalamin) or induced methemoglobinemia methemoglobinemia with nitrites and sodium thiosulfate.
100% O2, hyperbaric O2.
SIGNS/SYMPTOMS
Breath has bitter almond odor; cardiovascular collapse.
Headache, dizziness. Multiple individuals may be involved (eg, family with similar symptoms in winter). Classically associated with bilateral globus pallidus lesions on MRI A , although rarely seen with cyanide cyan ide toxicity as well.
Curve normal; oxygen saturation may appear normal initially. initially.
oxygen-binding
A
EFFECT ON OXYGEN�HEMOGLOBIN DISSOCIATION CURVE
capacity with left shift in curve, O2 unloading in tissues. Binds competitively competitively to Hb with 200× greater affinity than O2 to form carboxyhemoglobin. 20 Normal (100% Hb)
This illustration was edited in Pass 2
This illustration was edited in Pass 3
) 16 L m 0 0 1 / 2 O 12 L m ( b H o 8 t d n u o b
50% CO Hb 50% Hb (anemia)
2
O
4
0
0
20
40 60 PO2 (mm Hg)
80
100
RESPIRATORY
` RESPIRATORY�PATHOLOGY
SECTION III
Mediastinal pathology
Normal mediastinum contains heart, thymus, lymph nodes, esophagus, and aort a. Divided into compartments.
Mediastinal masses
Some pathologies (eg, lymphoma, lung cancer, abscess) can occur in any compartment, but there are common associations: Anterior— Anterior—4Ts: Thyroid, T hymic neoplasm, Teratoma, “ Terrible” lymphoma. Middle—esophageal carcinoma, metastases, hiatal hernia, bronchogenic cysts. Posterior—neurogenic tumor (eg, neurofibroma), multiple myeloma.
Mediastinal compartments Anterior
Middle
Posterior
659
Sternal angle
Superior mediastinum
Inferior mediastinum
Mediastinitis
Inflammation of tissues in the mediastinum. Commonly due to postoperative complications complications of cardiothoracic cardiothoracic procedures (pathology ≤ 14 days), days), esophageal perforation, or contiguous spread of odontogenic/retropharyngeal odontogenic/retropharyngeal infection. Chronic mediastinitis—also mediastinitis—also known as fibrosing mediastinitis; due to formation of connective tissue in mediastinum. Histoplasma capsulatum is common cause. Clinical features: fever, tachycardia, leukocytosis, chest pain, and (especially (especially with cardiac procedures) procedures) sternal wound drainage.
Pneumomediastinum
Presence of gas (usually air) in the mediastinum (black arrows show air around t he aorta, red arrow ar row shows air dissecting into the neck A ). Can either be spontaneous (due (due to rupture r upture of pulmonary bleb) or 2° (eg, trauma, iatrogenic, Boerhaave syndrome). Ruptured alveoli allow tracking of air into the mediastinum via peribronchial peribronchial and perivascular sheaths. Clinical features: chest pain, dyspnea, voice change, subcutaneous emphysema, ⊕ Hamman sign (crepitus on cardiac auscultation). Can be associated with pneumothoraces. pneumothoraces.
A
